Cystinosis: a review...Fig. 2 Typical growth charts in 2 cystinosis patients: a- Normal growth...

REVIEW Open Access

Cystinosis: a reviewMohamed A. Elmonem1,2, Koenraad R. Veys1, Neveen A. Soliman3,4, Maria van Dyck1,Lambertus P. van den Heuvel1,5 and Elena Levtchenko1*

Abstract

Cystinosis is the most common hereditary cause of renal Fanconi syndrome in children. It is an autosomal recessivelysosomal storage disorder caused by mutations in the CTNS gene encoding for the carrier protein cystinosin,transporting cystine out of the lysosomal compartment. Defective cystinosin function leads to intra-lysosomalcystine accumulation in all body cells and organs. The kidneys are initially affected during the first year of lifethrough proximal tubular damage followed by progressive glomerular damage and end stage renal failure duringmid-childhood if not treated. Other affected organs include eyes, thyroid, pancreas, gonads, muscles and CNS.Leucocyte cystine assay is the cornerstone for both diagnosis and therapeutic monitoring of the disease. Severallines of treatment are available for cystinosis including the cystine depleting agent cysteamine, renal replacementtherapy, hormonal therapy and others; however, no curative treatment is yet available. In the current review we willdiscuss the most important clinical features of the disease, advantages and disadvantages of the current diagnosticand therapeutic options and the main topics of future research in cystinosis.

BackgroundCystinosis was first described in literature in 1903 by theSwiss biochemist Emil Abderhalden (1877–1950) as thefamilial cystine accumulation disease [1]. Abderhaldenreferred to a child initially encountered by Eduard Kauf-mann, Basel, Switzerland (1860–1931). This patient diedat the age of 21 months with massive cystine accumula-tion in multiple organs that were discovered at the post-mortem examination. The Dutch pathologist GeorgeLignac (1891–1954) was the first to provide a clear sys-tematic description of the disease in 1924, and the firstto associate cystinosis with its major clinical manifesta-tions such as rickets, renal disease and growth retardation[2]. This is why cystinosis was initially termed as theAbderhalden-Kaufmann-Lignac syndrome. Guido Fanconi(1892–1979), the Swiss pediatrician, also substantiallycontributed to the understanding of cystinosis by explain-ing the urinary substance losing nature of the disease [3].Hence, cystinosis was also recognized in the literature asthe Lignac-Fanconi syndrome.The currently used term “cystinosis” is a modification

from the German term “Cystindiathese” or “hereditary cyst-ine disease” which was initially used by Emil Abderhalden

to describe the disease in 1903 and was modified in theEnglish literature to “cystine disease” then “cystinosis”.Cystinosis (ORPHA213) is a rare autosomal recessive lyso-somal storage disorder in which the amino acid cystineaccumulates in the lysosomes of cells [4]. Cystinosis is oneof the few rare diseases having a specific treatment. Theaminothiol cysteamine, used for the treatment of cystinosisfor over 20 years now [5], can deplete the intralysosomalcystine through the reduction of cystine, and the formationof cysteine and a cysteamine-cysteine mixed disulfide whichexits the lysosome via the cationic amino acid transporterPQLC2, thus bypassing the original genetic and biochem-ical defects of the disease [6, 7].Cystinosis is a systemic disease and cystine crystals, the

pathologic landmark, accumulate in all body cells and tis-sues. Although cystinosis is a monogenic disease, it hasthree major clinical presentations depending on the sever-ity of mutations affecting the CTNS gene: the infantilenephropathic form (MIM: 219800, ORPHA411629), thejuvenile nephropathic form (MIM: 219900, ORPHA411634) and the ocular non-nephropathic form (MIM:219750, ORPHA411641) [8].In the current review, we describe the clinical

spectrum of the disease, the diagnostic and managementprotocols and the anticipated advances in the nearfuture.

* Correspondence: [email protected] of Pediatric Nephrology & Growth and Regeneration, UniversityHospitals Leuven & KU Leuven, UZ Herestraat 49–3000, Leuven, BelgiumFull list of author information is available at the end of the article

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EpidemiologyNationwide birth prevalence data concerning cystinosis areonly reported in few populations. The overall incidencerates reported in France [9], Australia [10], Germany [11],Denmark [12] and Sweden [13] were 1:167,000, 1: 192,000,1: 179,000, 1:115,000 and 1:260,000 live births, respectively.Higher incidence rate is observed in selected populationswith detected founder mutations as in the province ofBrittany, France (1:26,000 live births) [14] or in theSaguenay-Lac-St-Jean, Quebec, Canada (1:62,500 livebirths) [15]. The highest birth frequency rate ever re-ported was in the Pakistani ethnic group living in theWest Midlands, UK (1: 3,600) [16]. Since cystinosis isan autosomal recessive disease, its incidence is expectedto be affected by the extent of consanguinity in the com-munity. Accurate statistical data about the incidence ofcystinosis in regions with high consanguinity such asMiddle East and North Africa are still lacking; however,cystinosis was fairly commonly detected among alarge cohort of different lysosomal storage disorders

diagnosed over a six year period in Egypt (29/211 pa-tients (13.7 %)) [17].

EtiologyCystinosis is caused by bi-allelic mutations in the CTNSgene (17p13.2) encoding cystinosin, which is a lysosomalcystine-proton co-transporter. Consequently, cystine ac-cumulates in the lysosomes of affected cells and formscrystals in low lysosomal pH [4].So far, over 100 pathogenic mutations have been re-

ported in the literature (Fig. 1). The most commonlydetected pathogenic mutation is the 57-kb deletionpresent in almost 50 % of CTNS mutant alleles of pa-tients of North European and North American origin[18, 19]; however, outside this geographical distribu-tion, the mutation is almost completely absent, espe-cially in the Middle East [20]. Severe or truncatingmutations on both alleles are usually associated withthe infantile severe form of the disease, while juvenileand ocular forms of cystinosis are usually associated

Fig. 1 Schematic representation of the CTNS gene and all reported mutations in cystinosis patients. Exonic mutations are displayed in the lowerhalf of the figure, while promoter and intronic mutations and large deletions are displayed in the upper half. INC: infantile nephropathiccystinosis, JNC: juvenile nephropathic cystinosis, OC: ocular cystinosis

Elmonem et al. Orphanet Journal of Rare Diseases (2016) 11:47 of 17

with at least one mild mutation. Genotypic-phenotypiccorrelations for the discovered CTNS mutations are sum-marized in Fig. 1.

Clinical description and complicationsRenal manifestationsThree clinical forms of cystinosis can be distinguished,depending on the age of presentation and the degree ofrenal disease severity.The infantile nephropathic form is the most frequent

(95 %) and the most severe type of cystinosis. The renalphenotype consists of renal Fanconi syndrome, and a con-secutively progressive loss of glomerular function leadingto end-stage renal failure [4, 21, 22]. Asymptomatic amino-aciduria is the first manifestation of renal Fanconi syn-drome in humans [23, 24] with urinary losses of aminoacids being 6 to 16 times increased compared to the nor-mal amount [25]. The earlier loss of expression of apicalproximal tubular receptors megalin/cubilin and SGLT-2,and NaPi-IIa transporters preceding cell atrophy in amouse model of cystinosis, provides an explanation for theearly proteinuria, glucosuria, and phosphaturia [26, 27].By the age of 6 to 12 months, selective proximal tubu-

lar dysfunction develops into the full-blown renal Fan-coni syndrome, characterized by excessive urinary loss ofamino acids, sodium, potassium, bicarbonate, magne-sium, carnitine, calcium, phosphate, glucose and lowmolecular (LMW) to intermediate molecular weight(IMW) proteins [23, 25]. Infants present with failure tothrive, polyuria, polydipsia, episodes of severe dehydra-tion and electrolyte imbalance, vomiting, constipationand sometimes vitamin D resistant rickets. Laboratory

findings may include hypokalemia, metabolic acidosis,hypophosphatemia, hypocalcemia, low carnitine levelsand less frequently hyponatremia. However, metabolicalkalosis in case of a Bartter-like presentation has alsobeen reported [28, 29].At birth, patients show a normal birth length and

weight parameters. By the age of 6 to 12 months, heightdrops to the third percentile, and further growth is re-stricted to less than 60 % of the normal range [8, 30, 31].Figure 2 represents the typical growth pattern of cystino-sis patients if specific treatment is not started in the firstyear of life. Calciuria and phosphaturia, in combinationwith phosphate, calcium, vitamin D and alkalinizingagent supplementation can cause medullary nephrocalci-nosis and nephrolithiasis in a subset of patients [32].Phosphaturia, increased urinary losses of vitamin Dbinding protein and decreased renal vitamin D conver-sion due to decreased activity of alpha-1 hydroxylase inrenal proximal tubules, can lead to vitamin D resistanthypophosphatemic rickets in children (Fig. 3) and os-teomalacia in adults [33]. Proteinuria is variable, andconsists initially of low molecular weight proteins (beta-2-microglobulin, alfa-1-microglobulin, retinol-bindingprotein) and intermediate weight proteins (albumin,transferrin, vitamin D binding protein). Glomerular pro-teinuria is present starting from early ages and is charac-terized by excessive urinary losses of albumin and HMWproteins, and may occur up to nephrotic range [34].Generally, serum creatinine levels remain within normallimits until the age of 5 years and only rarely exceed1 mg/dl below this age [8, 35]. If left untreated or iftreatment started late or even if the patient was not

Fig. 2 Typical growth charts in 2 cystinosis patients: a- Normal growth pattern at birth, followed by decreased growth velocity after six months.b- Progressive decrease in growth velocity in a patient who started cysteamine therapy after 2 years of age and was not treated with GH. Greenand blue lines represent the 3rd and the 97th percentiles for Height and weight, respectively. (Adapted with permission from Besouw andLevtchenko, 2010) [27]


compliant to treatment, end stage renal disease (ESRD)develops by the end of the first decade of life [36, 37].Due to the severe polyuria, episodes of dehydration canbe detrimental and usually accelerate the onset of ESRDat young age.A small group of cystinosis patients (5 %) is diagnosed

during late childhood or adolescence with the juvenile(late onset) form of cystinosis [38]. Patients present witha variable spectrum of features, ranging from isolatedasymptomatic proteinuria, a mild renal Fanconi syn-drome, to an overt nephrotic syndrome and usually theydo not develop remarkable growth retardation. Gener-ally, there is a slower progression rate to ESRD andextra-renal complications. In small series, four out of 14patients with juvenile cystinosis developed ESRD at 12,21, 27 and 28 years of age [38].The adult, non-nephropathic ocular form of cystinosis

is characterized only by photophobia due to cornealcystine accumulation, and rarely presents before adult-hood [39]. The kidneys and other organs are sparedfrom symptoms. In one family the co-existence of ocularand late-onset forms of cystinosis has been reported,implying the need of regular renal function controls inpatients with ocular cystinosis [38].

Extra-renal manifestationsBeing a systemic lysosomal storage disorder cystinosismanifests in almost all tissues and organs, and, althoughmost systemic features are manifested relatively lateduring the course of the disease, the pathological pro-cesses behind these manifestations, especially cystineaccumulation, usually start early. Nearly all nephropathic

cystinosis patients who did not receive early cystine-depleting therapy or those who are not compliant, willdevelop major extra-renal symptoms including retinal,endocrinological and neuromuscular complications bythe age of 30 years [40].Corneal cystine accumulation with crystal formation is

the first extra-renal finding affecting all cystinosis pa-tients [8]. It leads to photophobia and blepharospasmusually between mid-childhood to early adolescence. [8,41]. At birth, corneal cystine crystals are not detectable.They can only be observed from the age of 12 monthsthrough a slit lamp examination by an experienced oph-thalmologist and are always present by the age of18 months (Fig. 4). While superficial punctate and fila-mentary keratopathy is frequently seen in adolescentand adult patients, band keratopathy, peripheral cornealneovascularization and posterior synechiae associatedwith iris thickening are mostly found in older patients[42]. Depigmentation of the peripheral retina with pig-ment epithelial mottling is a commonly encounteredposterior segment complication [43]. It presents mainlyfrom the second decade of life, but has already been ob-served as early as at 6 months of age. In 10–15 % of pa-tients, retinopathy leads to retinal blindness [44].Progressive cystine accumulation and crystal formation

in thyroid follicular cells causes fibrosis and atrophyleading to primary hypothyroidism [45, 46], manifestingin the majority of cystinosis patients (50–70 %) from thesecond decade of life [30]. Earlier thyroid changesaffecting thyroglobulin synthesis and iodo-thyroglobulinprocessing might be responsible for subclinical hypo-thyroidism with TSH elevation and normal T3 and T4

Fig. 3 Rickets in cystinosis. a- A cystinosis child with evident rachitic bone deformities. b- Active rachitic bone disease in X-Rays


plasma concentrations, as it has been shown in a mousemodel of cystinosis [47].Endocrine and exocrine pancreatic insufficiency have

been also reported in cystinotic patients, usually afterrenal allograft transplantation [48, 49]. Fifty percent ofinfantile cystinosis patients by the age of 18 develop slowprogressive loss of insulin secretion and C-peptideproduction leading to glucose intolerance and diabetesmellitus [50]. Hepatomegaly and/or splenomegaly arepresent in about one third of patients by the age of15 years, however, liver function usually remains un-affected [48].In male cystinosis patients, primary hypogonadism is a

frequent finding (70 %) [51–53]. Recently, Besouw et al.have shown that although azoospermia was present inall studied male cystinosis patients under cysteaminetherapy, spermatogenesis was documented on a testicu-lar biopsy specimen in one renal transplant patient [54].In females, although delayed puberty is sometimes ob-served, normal pubertal development is also possibleand in contrast to males, cystinotic females are usuallyfertile [55].Central nervous system involvement is evident in a sub-

group of cystinotic patients and becomes more frequentwith advancing age. Neurological findings include hypo-tonia, tremor, speech delay, gross and fine motor impair-ment, idiopathic intracranial hypertension, neurocognitive

dysfunction, behavioral problems and encephalopathy[56–61]. Despite normal IQ scores, cystinosis patientshave significantly poorer performance in visual spatial andvisual memory skills than normal individuals and, interest-ingly, their highest scores are in the area of auditory short-term memory, which could be a compensatory mechan-ism for their poor visual memory [58, 62]. A recent studyin cystinosis patients aged 3–7 years, using the MRI basedtechnique, diffusion tensor imaging (DTI) detected theearly selective white matter microstructural changes in theform of bilaterally decreased fractional anisotrophy andincreased mean diffusivity in the inferior and superior par-ietal lobules in children with cystinosis corresponding tothe areas of the dorsal and ventral visual pathways [63],thus giving the pathological explanation for the early onsetof poor visual spatial and visual memory skills. Othercommon pathological findings usually observed at olderage include cerebral cortical atrophy, non-absorptivehydrocephalus, demyelination, and vacuolar, necrotic andspongiform changes [57, 58].A distal vacuolar myopathy presenting as progressive

distal muscle wasting and weakness, has been observedin about 24 % of renal transplant cystinosis patients[64, 65]. Myopathy generally affects patients from theirsecond decade of life. Myopathy changes on EMG can bepresent in asymptomatic patients, suggesting that clinic-ally overt muscle weakness might be a late sign of cystino-tic myopathy [60]. In post-transplant cystinotic patientswho did not receive long-term cystine-depleting therapy,cystinotic myopathy may cause an extraparenchymal pat-tern of restrictive lung disease [66]. Swallowing dysfunc-tion occurs in more than half of patients with myopathyand its severity also positively correlates with the numberof years without cysteamine therapy [67]. As a result,aspiration pneumonia constitutes a severe and potentiallylethal complication.Other observed features related to skin, hair and

salivary glands have also been reported such as congeni-tal hypopigmentation, premature skin ageing, impairedsweating and salivation and progressive coarse facial fea-tures due to subcutaneous cystine infiltration [68]. Ac-cording to our experience, not only European patients,but also some patients from other ethnic backgroundscan present with characteristic blond hair and whiteskin. Recently, cystinosin was implicated in the regula-tion of melanin synthesis as CTNS silencing in a melan-oma cell model led to over 50 % reduction in pigmentproduction [69].

Differential diagnosisAlthough cystinosis is the most common identifiablecause of the inherited renal Fanconi syndrome in children,other metabolic diseases (tyrosinemia, galactosemia, gly-cogen storage diseases), Wilson’s disease, Dent’s disease

Fig. 4 Corneal cystine crystals. Slit lamp examination of cornealcystine deposits (courtesy of Prof. Dr. Akmal Rizk, Dr. MohamedGamal and Prof. Dr. Neveen Soliman)


and Lowe’s syndrome should also be considered in the dif-ferential diagnosis of the renal Fanconi syndrome. Somecystinosis patients had atypical presentations and wereinitially diagnosed as Bartter’s syndrome or nephrogenicdiabetes insipidus [28, 29]. Most frequent genetic and ac-quired conditions for the differential diagnosis of cystinosisare summarized in Table 1.Cystinosis is also responsible for some cases of child-

hood renal failure, and should be considered in everyyoung patient presenting with renal failure of unknownorigin [37].

Diagnostic methodsDue to the availability of specific cysteamine therapy, earlydiagnosis and management of cystinosis have a great im-pact on the clinical outcome of patients. There are threemain diagnostic modalities for cystinosis. The current goldstandard is the detection of elevated cystine levels in whiteblood cells (WBCs), being extremely sensitive and precisefor the disease. Molecular testing of the relatively smallCTNS gene (12 exons but only 10 are coding) is also awell- established technique revealing 95 % of disease caus-ing mutations. The third clinically used confirmatory op-tion is the detection of the characteristic corneal cystinecrystals by slit lamp examination [27].Oshima et al. established a highly sensitive and specific

method for cystine measurement in WBCs in 1974 [70].Their assay was based on the selective binding betweencystine in the WBC sample and cystine binding protein(CBP) isolated from Escherichia coli in the presence of acompetitor external [14C] cystine, with the resultantbound radioactivity being inversely proportional to cyst-ine concentration in the unknown sample. Although stillused in few laboratories, this method is widely replacednow by high performance liquid chromatography(HPLC) or liquid chromatography-tandem mass spec-trometry (LC-MS/MS) methods [71, 72]. Newly diag-nosed cystinotic patients have WBC cystine levels in therange of 3–20 nmol half-cystine/mg protein, while con-trol individuals and heterozygous carriers have levels<0.2 and <1.0 nmol half-cystine/mg protein, respectively.The main source of the assay variability lies in themethod applied for WBCs separation, and whether it isa mixed leucocyte or polymorphonuclear leucocytepopulation, thus, the type of cells and the separationmethod should be highly standardized for each labo-ratory. Nevertheless, the instrumentations and tech-niques involved, so far, in cystine measurement aresophisticated enough to limit its use to few universityhospitals and research centers mainly in the devel-oped world. This is further complicated by the samplesensitivity to storage and transportation conditions,therefore so far most developing nations are still lack-ing the assay [73].

Being a monogenic disease, molecular diagnosis isefficient as a confirmatory tool; however, it is usuallymore time consuming than cystine measurement. Inabout 5 % of patients pathogenic mutations are noteasily discovered by the usual CTNS gene sequencing,being either deeply intronic, in the promoter regionor not commonly encountered large deletion or dupli-cation [74].The visualization of corneal cystine crystals is the main

diagnostic method for cystinosis in developing nations.Although reliable and relatively cheap, it needs a consid-erably experienced ophthalmologist to identify and gradethe crystals properly. Cystine crystals also do not appearin the slit lamp examination until the second year of lifewhich delays the start of specific therapy in most pa-tients [75].Another possible non-invasive evaluator of the cystine

crystal load is the reflectance confocal microscopy(RCM). Chiaverini et al. have shown that RCM is able todetect dermal cystine deposition in young patients withcystinosis [76]. Cystine deposits were visualized asbright, round, or oval-shaped dermal particles of variablesize. These particles appear to be specific in cystinosis,as no particles were identified in control subjects. Thenature of the deposits was further confirmed by electronmicroscopy showing that the particles corresponded tocrystalline cystine within fibroblasts in the reticular der-mis [76]. The test is rapid (5 min), painless and tolerableeven in the youngest children.Because of the availability of cystine-depleting therapy,

the development of a newborn screening method is verytempting; however, it is not available so far. The evalu-ation of cystine levels in blood spots would be logical toconsider but many technical difficulties stand in the wayincluding the much higher sensitive instrumentationneeded to quantify cystine reliably in a minute amountof sample (the current ideal sample for WBC cystine is5–10 ml of blood), the difficulty to prevent the spontan-eous oxidation of cysteine into cystine in stored bloodspots and the interference from serum cystine levelswhich are completely not related to the disease [77]. Arecent study has detected the elevation of sedoheptulosein dried blood spots of patients homozygous for the57-kb deletion mutation by tandem mass spectrom-etry [78]. This is the result of the simultaneous deletionof the CTNS upstream gene (CARKL/SHPK) which en-codes the enzyme sedoheptulokinase. Nonetheless, cysti-notic patients not harboring this mutation, or evenheterozygous would have a completely normal blood spotsedoheptulose levels, making the clinical use of thismethod very limited.Detection of most CTNS mutations is accomplished

by sequencing individual exons and the adjacent splicesites, while large deletions and insertions could be detected


Table 1 Differential diagnosis of cystinosis according to the most common presenting manifestations

Presentingmanifestations

Diseases MIM Gene Protein Other characteristic featuresat presentation

Proximal renaltubular acidosis

Tyrosinemia type I 276700 FAH Fumarylacetoacetase Hepatomegaly, mentalretardation

Galactosemia 230400 GALT Galactose-1-phosphateuridylyltransferase

Lethargy, jaundice, bleedingdisorders, cataract,intellectual disability

Hereditary fructoseintolerance

229600 ALDOB Aldolase B Seizures, irritability,poor feeding, lethargy,liver disease

Wilson disease 277900 ATP7B Copper transportingP-type ATPase

Liver disease,neuropsychiatricmanifestations, Kayser-Fleischer ring in the cornea

Lowe syndrome 309000 OCRL Phosphatidylinositol 4,5-diphosphate 5-phosphatase

Congenital cataract,glaucoma, intellectualdisability, hypotonia,seizures, behavioral problems

Dent’s disease 300009 CLCN5 Chloride Channel Proteinnumber 5

Low molecular weightproteinuria, hypercalciuria,nephrolithiasis,nephrocalcinosis, progressiverenal failure

Mitochondrialdisorders:

- Leigh syndrome 256000 COX10 Cytochrome C oxidaseassembly protein

Encephalopathy, myopathy,respiratory istress,deterioration of cognitivefunction

- Gracile syndrome 603358 BCS1L S. cerevisiae bcs1 proteinhomolog

Severe lactic acidosis,hypoglycemia, cholestasis,iron overload

- HUPRA syndrome 613845 SARS2 Seryl-t-RNA synthetase Hyperuricemia, pulmonaryhypertension, renal failure,alkalosis

- MitochondrialDNA depletionsyndrome 8

612075 RRM2B Ribonucleotide reductasesmall subunit 2 like

Neonatal hypotonia, lacticacidosis, neurologicdeterioration

- MitochondrialDNA depletionsyndrome 13

615471 FBXL4 Leucine rich repeat protein 4 Hypotonia, lactic acidois,microcephaly, congenitalcataract

Heavy metaltoxicity: Lead,cadmium

———————— ————————— —————————————————————————————————

Anemia, abdominal pain,encephalopathy,osteomalacia, neurologicalmanifestations

HypophosphatemicRickets

Hypophosphatemicnephrolithiasis/osteoporosis I

612286 SLC34A1 Sodium-phosphatecotransporter, member 1

Nephrolithiasis,osteoporosis, multiplefractures

Hypophosphatemicnephrolithiasis/osteoporosis II

612287 SLC9A3R1 Sodium/hydrogen exchangerregulatory factor 1

Nephrolithiasis,osteoporosis, hypocalcemia,hypoparathyroidism

Autosomaldominanthypophosphatemicrickets

193100 FGF23 Fibroblast growth factor 23 Fatigue, bony pains,bone deformities

Autosomal recessivehypophosphatemicrickets

241520 DMP1 Dentin matrix acidicphosphoprotein 1

Retarded skeletal growth,abnormal mineralization

Hereditaryhypophosphatemic

241530 SLC34A3 Sodium-phosphatecotransporter, member 3

Elevated serum 1,25-dihydroxy vitamin D levels,


by other molecular techniques such as allele specific PCR,multiplex ligation-dependent probe amplification (MLPA)or fluorescence in-situ hybridization (FISH) [79–81].Antenatal diagnosis of cystinosis through the detection

of elevated cystine in cells of fetal origin has been avail-able for many years now [82]. Two main sample typesare used for this purpose, either chorionic villous biopsysample (taken at 8–9 weeks of gestation) or cultured am-niotic cells (14–16 weeks of gestation). Cystine can bedirectly quantified in these cells with either HPLC or LC-MS/MS [83]. DNA analysis for detecting mutant alleles iscurrently the most frequently used antenatal screeningmethod, but to reach a molecular diagnosis in a timelyfashion for an informed decision, knowing the pathogenicmutation(s) in a previous sibling is highly favored.

ManagementOptimal symptomatic treatment of the renal Fanconisyndrome and extra-renal complications, combined withcysteamine, the specific cystine-depleting therapy repre-sent the mainstay of cystinosis treatment [84]. Earlydiagnosis is of vital importance to ensure better controlof cystinosis as the early start of specific treatment en-sures better growth and delays the onset of ESRD andmost of extra renal complications.

Symptomatic treatmentThe supportive, symptomatic treatment of cystinosisaims to (1) maintain an adequate fluid- and electrolytesubstitution and safeguard the acid–base balance, (2)provide nutritional support, (3) prevent the developmentof rickets and (4) ensure adequate substitution of neededhormones.Due to their polyuria and impaired sweating ability,

cystinosis patients should have access to water and toi-lets at all times, and should avoid excessive exposure toheat and sun in order to maintain proper hydration [27].Electrolyte substitution is provided through oral solu-tions of sodium bicarbonate or sodium/potassium cit-rate. Substitution with sodium or potassium phosphateand 1–25-(OH)2 cholecalciferol should be initiated fromearly childhood to compensate for the phosphate imbal-ance and to prevent rickets in patients with preservedGFR. Sodium, potassium, bicarbonate and phosphateneed to be monitored frequently, and the dose of substi-tution needs to be adjusted accordingly. If phosphate,1,25-(OH) 2 cholecalciferol and bicarbonate are exces-sively substituted, nephrocalcinosis may occur [85, 86].There is no consensus on the systematic use of indometh-acin in order to enhance sodium reabsorption at the as-cending limb of the loop of Henle and the collecting ducts

Table 1 Differential diagnosis of cystinosis according to the most common presenting manifestations (Continued)

rickets withhypercalciuria

hypercalciuria, osteomalacia,nephrolithiasis,nephrocalcinosis

Vitamin Ddependentrickets type I

264700 CYP27B1 25-hydroxyvitaminD3-1-alpha-hydroxylase

Hypotonia, muscle weakness,seizures

Vitamin Ddependentrickets type II

277440 VDR vitamin D receptor Alopecia, hypocalcemia,secondaryhyperparathyroidism,osteomalacia, osteitisfibrosa cystica

Stunted growth Cystic fibrosis 219700 CFTR Cystic fibrosis transmembraneconductance regulator protein

Frequent chest infections,pancreatic insufficiency

Chronicmalnutrition

———————— ————————— —————————————————————————————————

Fatigue, anemia, poorcognitive function,behavioral changes, historyof poor socioeconomicstandard

Hormonal causes

- Hypothyroidism ———————— ————————— —————————————————————————————————

Lethargy, fatigue, dry skin,cold intolerance,constipation, mentalsubnormality

- GH deficiency ———————— ————————— —————————————————————————————————

Short stature with generalgood health, normalintelligence

Familial ———————— ————————— —————————————————————————————————

Family history


[85]; however, this treatment can be useful to decreasepolyuria and reduce electrolyte losses.Carnitine replacement has been suggested because of

low plasma and muscle carnitine levels in cystinosis pa-tients, though clinical improvement with this therapyhas not been proven yet [87, 88]. The majority of cysti-nosis patients experience a progressive failure to thrivefor which a high-caloric diet is recommended in associ-ation with other lines of treatment [89]. Feeding bynasogastric tube should be considered early, especially inchildren with anorexia, complaints of anorexia and fre-quent vomiting, or to facilitate administration of medicaltreatment.Because of the multiple endocrinopathies caused by

cystinosis, hormone replacement therapy plays an im-portant role in symptomatic care. Careful monitoring ofthe thyroid, and later pancreatic function during child-hood and adolescence, is important. In the absence ofpoor cystine-depleting therapy and renal insufficiency,growth hormone replacement therapy can be consideredto prevent growth retardation despite a normal growthhormone axis [90]; however, the long term implicationsof growth hormone replacement in patients with cysti-nosis is unclear. Currently, insufficient data is availableon the pathophysiology of the azoospermia observed inmale cystinosis patients. Testosterone supplementationis indicated in patients with a primary testicular failureand low plasma testosterone levels [54].Angiotensin converting enzyme inhibitors (ACE inhibi-

tors) are a well-established treatment to reduce protein-uria of glomerular origin and to slow down the decline ofglomerular filtration rate in chronic renal failure. Greco etal. reported over 20 years of follow up in cystinosispatients, during which the use of ACE inhibitors was asso-ciated with slower deterioration of renal function [91];however, because of the risk of hypotension and conse-quent renal function decline, ACE inhibitors must be usedwith caution in patients with extracellular volume and so-dium depletion [92]. The combined use of ACE inhibitorstogether with indomethacin should be strictly avoided.In case of renal failure, renal transplantation is the

treatment of choice. As renal disease does not recur inthe transplanted kidney, kidney graft cures the ESRD,but has no effect on the multi-systemic complications.Therefore, cystine-depleting therapy has to be taken life-long. Although cystine crystals have been observed inthe renal graft, they are of no pathological nor clinicalsignificance since they arise from the host mononuclearcells [93]. In comparison to other renal diseases, renalgraft survival in cystinotic patients has been reported assuperior, although this has not been demonstrated inERA-EDTA registries [94–97].Since fluid and electrolyte losses generally decrease

during renal replacement therapy, nephrectomy of the

native kidneys is rarely needed. As other post-transplantpatients, all cystinosis patients should be monitored forimmunodeficiency and infections related to immunosup-pressive agents after renal transplantation.

Cystine-depleting therapyThe aminothiol cysteamine (beta-mercaptoethylamine)is currently the only target-specific treatment for cysti-nosis patients. It aims to deplete lysosomal cystine in allbody cells and tissues. The most commonly used cyste-amine preparation is the immediate-release cysteamine bi-tartrate (IR-CYS) (Cystagon®, Mylan Pharma, Morgantown,WV, USA and Orphan Europe, Paris, France). The drughas been approved for clinical use in cystinosis in 1994 inthe USA, and in 1997 in Europe [98].Cysteamine improves overall prognosis by delaying the

progression to end-stage renal disease by 6 to 10 years,and thus the need for renal transplantation during child-hood [8, 30, 85, 99–103]. Cysteamine has also beenshown to prevent or postpone the development of someextra-renal complications. It reduces the need for thy-roid hormone replacement therapy, depletes the muscleparenchyma of cystine hereby reducing myopathy, delayspulmonary and pancreatic dysfunction and preventsgrowth failure when initiated in early infancy [30, 99–101].In a large cohort of adult cystinotic patients, the frequencyof diabetes and myopathy decreased from 28 % to 0 % andfrom 60 % to 0 %, respectively when the duration of cyste-amine treatment exceeded 20 years, while the percentageof hypothyroidism decreased from 87 % to 56 % in patientshaving cysteamine for more than 8 years [100].Cysteamine has been shown to prevent growth retard-

ation if initiated in early infancy [31, 97, 104]. However, itis unable to induce a catch-up growth when growthretardation has already set in [90, 91]. Figure 5 demon-strates the importance of early cysteamine therapy to pre-vent growth retardation. Therefore, cysteamine treatmentshould be started as soon as possible, and needs to becontinued lifelong. In general, the effect of cysteamine ininfantile cystinosis is at its best when treatment is initiatedin the first year of life, compliance was maintained andleucocyte cystine levels were kept below 1 nmol ½ cystine/mg protein [36]. However, Oral cysteamine has no effecton the renal Fanconi syndrome, male infertility or cornealcystine accumulation [8]. Topical cysteamine therapycan be used to dissolve the corneal cystine crystals,thus treating the photophobia. Cysteamine eye dropsare recommended to be used frequently (>10 timesper day), but due to acidic formulation are frequentlyassociated with a burning sensation that is especially an-noying for children, hampering the compliance. An oph-thalmic gel formulation has been recently developed(Cystadrops®, Orphan Europe, Paris, France) and provento be effective when administered 4 times a day (0.55 %,


one drop in each eye per dose) [105]. Ocular symptomshave shown to improve in a couple of weeks, and corneasbecome clear within few months.The leucocyte cystine level is today the only available

biomarker for monitoring the effectiveness of oralcystine-depleting therapy. The tissue cystine levels atwhich progressive renal failure and extra-renal complica-tions can be prevented, are unknown. Hence, the 90thpercentile of cystine levels in polymorphonuclear cells(<1 nmol ½ cystine per mg protein), seen in heterozy-gotes, is used as the upper cystine limit. The leucocytecystine content returns to its initial levels about 6 h afterthe last administration, therefore the immediate releaseformulation of cysteamine bitartrate (IR-CYS) has to betaken at a 6-h interval. Greater compliance with oralcysteamine therapy yields greater preservation of renalglomerular function as for every year of excellent cystinedepletion, nearly one year of renal function was pre-served [106].Cysteamine is a potent gastric acid-secretagogue and

has been used to induce duodenal ulceration in laboratory

animals [85]. In children, a fourfold increase in gastric acidproduction and 50 % increase in serum gastrin levelsin comparison to baseline levels, have been reported[107, 108]. Hence, gastrointestinal complaints as nausea,dyspepsia, vomiting and epigastric pain are frequent andcause cysteamine intolerance in approximately 14 % of pa-tients [30, 99, 109]. In our experience, these complaintscan be minimized by the low start and gradual increase incysteamine dosage. Use of proton pump inhibitors hasbeen found effective in the management of gastric acid hy-persecretion and ulcerogenicity [110]. In selected patients,a Nissen fundoplication may be of help. A small amountof cysteamine is also metabolized into sulfur-containingcompounds (dimethylsulfide, methanethiol), which causehalitosis and a bad sweat odor. For this, oral supplementsof riboflavin and chlorophyll tablets are used by some pa-tients [84, 111].It has been suggested to calculate the cysteamine dose

based on body surface area (1.30 g/m2/day; maximum of1.95 g/m2/day) instead of body weight (50 mg/kg/day),to avoid overdosing [112]. Recently, some patientstreated with high cysteamine doses (>1.95 g/m2/day)were reported to have skin striae, bone pain, myalgia,and endothelial proliferative lesions on the elbows showingreactive angioendotheliomatosis on skin biopsy. These ad-verse events developed in a small proportion of patients,and, while bone and joint pain remained in some patients,cutaneous manifestations resolved after lowering the doseof cysteamine [113].Other reported adverse effects of cysteamine include

hyperthermia, lethargy, neutropenia, seizures and aller-gic rash [114]. Fortunately, these effects are reversible,and when cysteamine is started at a low dose and in-creased gradually, these complaints can be prevented[114]. Based on the observation of dose-related (100–150 mg/kg/day) development of a cleft palate, kyphosis,intrauterine growth retardation and intrauterine deathwith cysteamine treatment in the rat, it is recommendedto discontinue cysteamine in women planning pregnancy[115, 116]. The potential risks of cysteamine discontinu-ation for several months should be carefully balancedagainst the desire to have children.Taken together, current cysteamine therapy with its

strict dosing regimen and significant adverse effects, im-poses a significant burden on cystinosis patients. It hasbeen estimated that only one third of patients areable to adhere to the strict dosing schedule [102].Poor compliance leads to a less favorable prognosiswith progressive renal function deterioration and poorgrowth [109].Recently, a new twice-daily delayed-release enteric-

coated formula of cysteamine bitartrate (DR-CYS) (Pro-cysbi™, Raptor Pharmaceuticals Inc., Novato, CA, USA)has been approved for clinical use by the US Food and

Fig. 5 The effect of cysteamine treatment in two siblings withnephropathic cystinosis. The growth in the 30-months old youngersibling (right side, 86 cm, 11.5 kg) who received pre-symptomaticcysteamine therapy at 3 months of age exceeded that of his56-months old elder brother (left side, 80 cm, 10.5 kg) with laterdiagnosis and treatment at the age of 20 months (courtesy ofDr. Rasha Helmy and Prof. Dr. Neveen Soliman)


Drug Administration (FDA) and European MedicinesAgency (EMA) in 2013 for the treatment of cystinosis. Itwas developed based on the observation that direct ad-ministration of cysteamine in the small intestine resultedin higher plasma concentrations and a higher area underthe curve in comparison to administration in the stom-ach or colon [117]. It has been hypothesized that thegreater surface area and the improved absorption ratefrom the small intestine, and less first pass metabolism,can explain this finding [118]. This new formulationconsists of an enteric-coated capsule, containing micro-spheronized beads. It only needs to be administeredtwice daily, instead of four times daily. DR-CYS has thepotential to improve compliance through its better dos-ing regimen. Table 2 provides the most important guide-lines for the management of cystinosis [84].

Therapeutic monitoringThe current gold standard in the therapeutic monitoringof cystinotic patients is the WBC cystine assay. Theoretic-ally, a more specific and ideal therapeutic monitor wouldbe the direct assessment of the fluctuating lysosomal cyst-ine load in different tissues in response to treatment; how-ever, the invasiveness of tissue samples is prohibitive,especially in children. WBCs offer the second best option,and since cystine accumulates preferentially in poly-morphonuclear leucocytes but not in lymphocytes,granulocyte separation is preferred to a mixed leucocytepopulation [119]; however, the large blood volume needed,the analyte instability during transportation, the difficulttechnique and the unavailability of the assay in manycountries, all make the WBC cystine assay far from beingperfect as a therapeutic monitor. Furthermore, the ex-tremely short life span of polymorphonuclear leucocytes(≈12 h) might not be ideal for the long term follow-up inpatients with unstable compliance [77].Recently, several non-invasive immunological markers

have been proposed to assess the disease activity upondiagnosis and during follow up of cysteamine treatment.The immune system is expected to play a major role inthe pathogenesis of nephropathic cystinosis and its rapidprogression to ESRD unlike other types of hereditaryFanconi syndromes. Prencipe et al. detected the stimula-tion of the inflammasome related cytokines: IL-1β, IL-6and IL-18 in human peripheral mononuclear cells whenexposed to cystine crystals, in the plasma of cystinoticpatients and in the serum and tissues of Ctns knocked-out mice [120]. On the other hand, we reported the sig-nificant elevation of the macrophage marker chitotriosi-dase in cystinotic patients. Moreover, control humanmacrophages were potently activated in vitro when ex-posed to different concentrations of cystine crystalsthrough the significant elevations of TNF-α and chitotrio-sidase in both supernatant and cell lysate. Chitotriosidase

activities were also significantly elevated in the plasma ofcystinotic knocked-out versus wild-type mice [73]. Theseimmune based markers could be promising indirect indi-cators of the disease severity and hence the response totreatment, as the cystine crystal accumulation in cystinosisis the main motive behind their release. Besides, they aremuch more stable and less technically demanding thanthe WBC cystine assay. Another possible therapeuticmonitor of the cystine crystal load needing further evalu-ation is the in vivo reflectance confocal microscopy of theskin [76].

PrognosisSince it was first reported in early twentieth century,prognosis of cystinosis has improved dramatically, par-ticularly with the advent of cystine-depleting treatmentand renal replacement therapy (dialysis and kidneytransplantation) in the early 1980s. Consequently morepatients are increasingly growing into adulthood insteadof succumbing to ESRD by late 1st or early 2nd decadeof life. With the increased life expectancy more long-term complications are being recognized and reported,that did not have enough time to evolve in the pediatricage group [100].North American Pediatric Renal Transplant Cooperative

Study suggests that the outcome of renal transplantationis favorable in patients with a primary diagnosis of cysti-nosis [94]. A large European observational registry studyreported a significant delay in the age of initiation of renalreplacement therapy in nephropathic cystinosis patients(0.15 year per calendar year, 95 % confidence interval:0.1–0.21 year) which wasn’t observable in a matched co-hort of non-cystinotic pediatric patients who started renalreplacement therapy in the past 2 decades [101]. In anadult patient cohort, renal transplant recipients with cysti-nosis had a better long-term outcome than other renaltransplant recipients. Authors confirmed, by multivariateanalysis, that cystinosis is an independent protective factorfor graft survival [96].Nowadays cystinosis is increasingly being diagnosed at

younger age allowing early and adequate initiation ofcystine-depleting therapy which significantly prevents, orat least delays, the complications of the disease. Thatbeing said, adherence to therapy is critical to improvedclinical outcomes. In patients with poor compliance tofrequent dosing formulation, the administration of thenewly developed delayed-release formulation is likely toimprove patient compliance resulting in fewer long-termcomplications of cystinosis and improved quality of life.Even though cystinosis does not recur in the graft afterrenal transplantation, yet it continues to progress inother organs and tissues causing complications that mayworsen the prognosis, hence the need to continue cyste-amine therapy even after kidney transplantation.


Table 2 Treatment guidelines for cystinosis

Medication Daily dose Frequency Remarks

Symptomatic treatment

Renal Fanconi syndrome

Polyuria Free water supply Day and night Special attention for sufficient hydration incase of fever, diarrhea and external heat

Early tube feeding may be needed for waterrequirements

Malnutrition high caloric intake 130 % of RDI Tube feeding can be needed in young infants

Renal salt loosing sodium citrate or sodiumbicarbonate

Oral 2–10 mmol/kg QID Between meals

Alkali losses citrate or bicarbonate assodium & potassium salts

Oral 5–15 mmol/kg QID Normal bicarbonate level (21–24 mmol/l)should be achieveda

Potassium losses potassium citrate or potassiumchloride

Oral 2–10 mmol/kg QID Potassium level > 3 mmol/l should beachieveda

Phosphate losses sodium or potassiumphosphate

Oral 30–60 mg elementaryP/kg

QID Normal age-related phosphate levels shouldbe achieveda

High doses of phosphate supplements cancause or aggravate nephrocalcinosis

Treatment of rickets calcidiol Oral 10–25 μg QD Follow-up serum calcium concentration toprevent hypercalcemia

alpha-calcidol or calcitriol Oral 0.04–0.08 μg/kg

Copper deficiency copper supplementation no data is available incystinosis

1–10 mg/day depending on age andserum copper levels

Chlorophyllin tablets that are used to mitigatehalitosis contain 4 mg of elemental copperper tablet

Difficult to controlelectrolyte lossesand polyuria

indomethacin Oral 1–3 mg/kg BID Follow-up serum creatinine

Discontinue in case of dehydration

Concomitant use with ACE inhibitors iscontra-indicated

Carnitine losses L- carnitine Oral 20–50 mg/kg TID Not proven effect on clinically relevant musclehealth

Proteinuria ACE-inhibitors (enalapril) Oral 0.10–0.25 mg/kg(for enalapril)

QD Control serum creatinine and potassiumadministration at night to avoid hypotensioncomplaints

Concomitant use with Indomethacin iscontra-indicated

Hormonal substitution

Hypothyroidism levothyroxin Oral QD Start by 25 % of the recommended doseand increase to full dose in 4 weeks

<12 years:5 μg/kg

>12 years: 2–3 μg/kg

Adults: 1.7 μg/kg

Growth retardation rhGH SC 0.05 mg/kg QD Early initiation when growth failure persistsafter optimal control of feeding, electrolytesand rickets

Higher doses of phosphate supplementationmay be needed

Glucose intolerance insulin SC (cfr endocrinology) Control by blood glucose

Regular control of Hb A1C


Future prospects and unresolved questionsRecent studies linked cystinosin deficiency in cystinosisto other pathophysiologic mechanisms not related tocystine accumulation such as altered vesicle traffickingand impaired mTOR signaling [121–123], thus a betterunderstanding of the pathogenic mechanisms of cystino-sis is highly needed to plan and develop more efficienttherapeutic targets. Multiple cell and animal cystinoticmodels have been developed to better understand andcharacterize the different phenotypic features of the dis-ease. Immortalized cell lines for cystinotic proximal tubu-lar epithelial cells and podocytes have been establishedand sustained from either biopsy material or exfoliatedcells in urine [122–125]. The mouse model for cystinosishas been also available for over a decade now [126]. Al-though, it can accumulate cystine in most organs, manyimportant phenotypic features like tubulopathy and renalfailure were not expressed in the initial model. A secondmouse model was later developed on a pure C57BL/6background that avoided some of the pitfalls of the firstone [127]. These cell and animal models provide indis-pensable tools to study pathologic and molecular mecha-nisms of the disease. They can be also used to evaluate thein vitro and in vivo responses to experimental new thera-peutic drugs and different therapeutic strategies.With the current rapid advance in the technology of

tandem mass spectrometry, the sensitivity of recent ma-chines are almost two to three orders of magnitude theolder ones, thus the development of a suitable methodfor the newborn screening of cystinosis can be applicablein the near future. An interesting approach is the quanti-fication of the deficient protein cystinosin by peptide

Immunoaffinity enriched LC-MS/MS analysis. Thetechnology has already been applied for the detectionof signature proteins for three primary immuno-deficiency diseases: severe combined immunodeficiency(SCID), Wiskott–Aldrich syndrome (WAS), and X-linkedagammaglobulinemia (XLA) [128].Although, the newly investigated diagnostic markers

look promising for the monitoring of disease activity andtreatment response [73, 76, 120], longitudinal clinicalstudies are strongly needed to validate these observa-tions. Laboratory markers as chitotriosidase and inter-leukins, while being much easier to sample and measurethan WBC cystine, are not strictly specific for cystinosis,thus sensitivity and specificity issues need to be handledcarefully before determining their utility as therapeuticmonitors. On the other hand, the monitoring of the invivo dermal cystine crystals by confocal microscopy,while being extremely specific for the disease, needs agreat deal of experience to operate the instrument andinterpret the results. Whether this experience can beavailable for routine clinical use or not, only the futurecan tell.The search for therapeutic substitutes for cysteamine

is now strongly ongoing. Adverse effects and complianceissues are still hindering the full capacity of the drugeven after the development of the longer acting formula-tion. The therapeutic focus now is not just cystine deple-tion, but also how to alleviate other possible harmfulpathogenic mechanisms in cystinosis such as inflam-mation, autophagy and oxidative stress [120, 129, 130].New promising therapeutics that can target these differ-ent disease mechanisms are being currently evaluated in

Table 2 Treatment guidelines for cystinosis (Continued)

Cysteamine treatment

Systemicadministration

immediate release cysteaminebitartrate (Cystagon®)

1.30–1.95 g/m2 QID Start at low dose (1/6 th of optimal dose),gradual increase over 6–8 weeks

delayed release cysteaminebitartrate (Procysbi®)

Start with 80 % of theimmediate-release form

BID Gastrointestinal complaints: add protonpomp inhibitors

Skin lesions (striae, molluscoid tumor atelbows): dose reduction by 25–50 %,control for copper deficiency

Regular dosing of WBC cystine levels(children x4 per year, adults x1-2 per year)b

Corneal cystine crystals cysteamine eye drops 0.5 % topical application 8–10 time daily Yearly eye examination

cysteamine eye gel(Cystadrops®)

QID

Varia

Gastro-intestinalcomplaints

Proton pump inhibitorsomeprazole

<10 kg: 1- mg/kg BID

10–20 kg: 10–20 mg BID

>20 kg: 20–40 mg BIDaTrough levels of electrolytes and phosphate (before the administration of the next dose) should be measuredbBlood for the determination of WBC cystine levels should be taken 6 h after Cystagon® and 12 h after Procysbi® administration


cell and animal models. Hematopoietic stem cell trans-plantation in humans is another interesting therapeuticoption, raising new hopes in finding a cure for cystinosisand further improving long-term clinical outcomes. Beinghighly successful in the mice model [131, 132], therapeutichuman trials are currently being planned but whether it isgoing to be as successful and safe in humans as in mice, isyet to be determined.

ConclusionsCystinosis is a systemic disease that needs a multilevelclinical collaboration to rapidly diagnose and properlytreat. The current diagnostic and therapeutic regimensmade it possible for the transition of most cystinotic pa-tients to adulthood; however, the search for more effi-cient screening and better therapeutic options throughunravelling the basic pathogenic mechanisms of the dis-ease will surely hold the promise to a better future.

ConsentWritten informed consents were obtained from patients’parents for the publication of images in this report.

Competing interestsThe authors declare that they have no competing interests.

Authors’ contributionMAE and EL put the design and layout of the manuscript. MAE, KRV, NAS,MV, LPV and EL drafted the manuscript. MAE and NAS prepared the figures.MV prepared the treatment guideline table. All authors read and approvedthe final manuscript.

AcknowledgementsElena Levtchenko is supported by the Research Foundation - Flanders(F.W.O. Vlaanderen), grant 1801110 N. Mohamed A. Elmonem is supportedby ERA-Net E-Rare2 JTC2014. Koenraad R. Veys is supported by the ResearchFoundation - Flanders (F.W.O. Vlaanderen), grant 11Y5216N.

Author details1Department of Pediatric Nephrology & Growth and Regeneration, UniversityHospitals Leuven & KU Leuven, UZ Herestraat 49–3000, Leuven, Belgium.2Department of Clinical and Chemical Pathology, Faculty of Medicine, CairoUniversity, Cairo, Egypt. 3Department of Pediatrics, Center of PediatricNephrology and Transplantation (CPNT), Faculty of Medicine, CairoUniversity, Cairo, Egypt. 4EGORD, Egyptian group of orphan renal diseases,Cairo, Egypt. 5Department of Pediatric Nephrology, Radboud UniversityMedical Center, Nijmegen, The Netherlands.

Received: 28 October 2015 Accepted: 15 April 2016

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